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WO2018138267A1 - Procede de determination de l'efficacite d'une composition comprenant le g-csf - Google Patents

Procede de determination de l'efficacite d'une composition comprenant le g-csf Download PDF

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Publication number
WO2018138267A1
WO2018138267A1 PCT/EP2018/051965 EP2018051965W WO2018138267A1 WO 2018138267 A1 WO2018138267 A1 WO 2018138267A1 EP 2018051965 W EP2018051965 W EP 2018051965W WO 2018138267 A1 WO2018138267 A1 WO 2018138267A1
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Prior art keywords
csf
containing composition
blood glucose
glucose level
administration
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PCT/EP2018/051965
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English (en)
Inventor
Karsten Roth
Rüdiger JANKOWSKY
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Cinfa Biotech S.L.
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Publication of WO2018138267A1 publication Critical patent/WO2018138267A1/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6863—Cytokines, i.e. immune system proteins modifying a biological response such as cell growth proliferation or differentiation, e.g. TNF, CNF, GM-CSF, lymphotoxin, MIF or their receptors
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/66—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving blood sugars, e.g. galactose
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/52—Assays involving cytokines
    • G01N2333/53—Colony-stimulating factor [CSF]
    • G01N2333/535—Granulocyte CSF; Granulocyte-macrophage CSF
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/22—Haematology

Definitions

  • the present invention relates to a method for determining the efficacy of a granulocyte-colony stimulating factor (G-CSF) containing composition comprising the steps of measurement of the blood glucose level of at least one sample obtained from a subject to which a G-CSF containing composition was administered, determining the efficacy of the G-CSF containing composition based on the blood glucose level.
  • the present invention further relates to a method for determining the efficacy of a granulocyte-colony stimulating factor (G-CSF) containing composition comprising the steps of administration of the G-CSF containing composition to a subject, measurement of the blood glucose level of said subject and determining the efficacy of the G-CSF containing composition based on the blood glucose level.
  • G-CSF granulocyte-colony stimulating factor
  • G-CSF also known as colony-stimulating factor 3 (CSF 3), belongs to the hormone family of cytokines. The glycoprotein stimulates production of neutrophil precursors and the
  • G-CSF is used for the treatment of fibril neutropenia a common complication in patients receiving myelo suppressive chemotherapy.
  • the efficacy of the G-CSF comprising composition has to be determined, for example for the assessment of new G-CSF variants or for the determination whether the G-CSF comprising composition shows a treatment effect in a specific patient.
  • One possibility is to determine the efficacy of G-CSF by counting of neutrophils.
  • this elaborate method is costly. Therefore, there is a need for a simple method that measures the efficacy of G-CSF shortly after the administration.
  • a first aspect of the invention refers to a method for determining the efficacy of a granulocyte-colony stimulating factor (G-CSF) containing composition, comprising the steps of measurement of the blood glucose level of at least one sample obtained from a subject undergoing a G-CSF treatment, determining the efficacy of the G- CSF containing composition based on the blood glucose level.
  • G-CSF granulocyte-colony stimulating factor
  • the invention relates to method for determining the efficacy of a granulocyte- colony stimulating factor (G-CSF) containing composition, wherein the method comprises the following steps:
  • Another aspect of the invention relates to a method for determining the efficacy of a granulocyte-colony stimulating factor (G-CSF) containing composition, comprising the steps of administration of the G-CSF containing composition to a subject, measurement of the blood glucose level of said subject and determining the efficacy of the G-CSF containing composition based on the blood glucose level.
  • G-CSF granulocyte-colony stimulating factor
  • the measurement of the blood glucose level of the subject is carried out before and after the administration of the G-CSF containing composition.
  • G-CSF is selected from the group consisting of filgrastim, pegfilgrastim, lenograstim and lipegfilgrastim. More preferably, the G-CSF is pegfilgrastim.
  • the measurement of the blood glucose level after the administration of the G-CSF containing composition may be carried out 12 hours to 144 hours after the administration of the G-CSF containing composition.
  • the measurement of the blood glucose level after the administration of the G-CSF containing composition is carried out 36 h to 72 h after the administration of the G-CSF containing composition.
  • the subject is suffering from neutropenia.
  • neutropenia is caused by cytotoxic chemotherapy which the subject receives.
  • a decrease of the blood glucose level below a predetermined threshold after the administration of the G-CSF containing composition level indicates that the G-CSF containing composition is efficacious.
  • a decrease of the blood glucose level by a predetermined value or predetermined percentage after the administration of the G-CSF containing composition indicates that the G-CSF containing composition is efficacious.
  • a blood glucose level decrease by at least by 0.4 mmol/1, preferably by at least 0.5 mmol/1, more preferably by at least 0.8 mmol/1, even more preferably by at least 1 mmol/1 may indicate that the G-CSF containing composition is efficacious.
  • a blood glucose level decrease by at least 5 %, preferably by at least 10 %, more preferably by at least 15 %, even more preferably by at least 20 % indicates that the G-CSF containing composition is efficacious.
  • the blood glucose level may be measured under fasting or non- fasting conditions, preferably under fasting conditions.
  • the invention refers to a method for determining the efficacy of a granulocyte-colony stimulating factor (G-CSF) containing composition, comprising the steps of measurement of the blood glucose level of at least one sample obtained from a subject undergoing a G-CSF treatment (e.g. to which a G-CSF containing composition was administered), determining the efficacy of the G-CSF containing composition based on the blood glucose level.
  • the invention relates to method for determining the efficacy of a granulocyte-colony stimulating factor (G-CSF) containing composition, wherein the method comprises the following steps:
  • the efficacy of the G-CSF containing composition may be determined by comparison of the blood glucose level of the at least one reference sample obtained from the subject with the blood glucose level of the at least one sample obtained from the subject after the administration of the G-CSF containing composition.
  • the invention relates to method for determining the efficacy of a granulocyte- colony stimulating factor (G-CSF) containing composition, wherein the method comprises the following steps:
  • the efficacy of the G-CSF containing composition may be determined by comparison of the blood glucose level of the at least one sample obtained from a subject before the administration of the G-CSF containing composition with the blood glucose level of the at least one sample obtained from the subject after the administration of the G-CSF containing composition.
  • the invention refers to a method for determining the efficacy of a granulocyte-colony stimulating factor (G-CSF) containing composition, comprising the steps administration of the G-CSF containing composition to a subject, measurement of the blood glucose level of said subject and determining the efficacy of the G-CSF containing composition based on the blood glucose level.
  • G-CSF granulocyte-colony stimulating factor
  • the blood glucose level can be used to determine the efficacy of the G-CSF containing composition, since after administration of the G-CSF containing composition a decrease in the blood glucose level occurs. This may due to the fact that G-CSF increases the generation of neutrophils which in turn increases metabolism.
  • the invention refers to a method for determining the efficacy of a granulocyte-colony stimulating factor (G-CSF) containing composition, comprising the steps of administration of the G-CSF containing composition to a subject, measurement of the blood glucose level of said subject and determining the efficacy of the G-CSF containing composition based on the blood glucose level.
  • G-CSF granulocyte-colony stimulating factor
  • the value of the blood glucose level after the administration of the G-CSF containing composition is used for the determination of the G-CSF containing composition.
  • the blood glucose level of less than 4.5 mmol/1, preferably less than 4.25 mmol/1, more preferably less than 4.0 mmol/1 under fasting conditions may indicate that the G-CSF containing composition is efficacious.
  • a reference sample is not required.
  • the decrease of the glucose level after the administration of the G-CSF containing composition is used in the method of the invention. That means that the blood glucose level after the administration of the G-CSF containing composition, i.e. the glucose level of the at least one sample obtained after the administration of G-CSF, is compared to the blood glucose level before the administration, i.e. the glucose level of the at least one sample obtained before the administration of G-CSF.
  • the blood glucose level before and after the administration of the G-CSF containing composition is measured and the decrease of the blood glucose level after the administration of the G-CSF containing composition is determined by the subtraction of the blood glucose level after the administration from the blood glucose level in the reference sample, typically the at least one sample obtained before the administration.
  • the blood glucose level is measured before the G-CSF containing composition is administered to the subject.
  • the blood sugar value that serves as reference without the administration of the G-CSF containing composition could even been measured in a sample obtained shortly after administration of G-CSF, in an interval in which G-CSF is not showing an effect or is not expected to show an effect, i.e. in an interval of less than one hour after the administration of the G-CSF containing composition.
  • measurement before the administration and measurement after the administration describes the time point of the sample collection relative to the administration of the G-CSF containing composition. That means that the blood glucose level that is measured before the administration is collected before the administration of the G-CSF containing composition but the measurement of the glucose level of said sample may be carried out at a later time point which might be after the administration of the G-CSF containing composition.
  • the "reference sample” may be a sample which is which is obtained from a subject before the administration of the G-CSF containing composition as defined above and/or obtained shortly after administration of G-CSF, in an interval in which G-CSF is not showing an effect or is not expected to show an effect, i.e. in an interval of less than one hour after the administration of the G-CSF containing composition.
  • the method comprises the following steps:
  • the method comprises the following steps:
  • step (i) occurs before the administration of the G-CSF containing composition and step (iii) occurs after the administration of the G-CSF containing composition.
  • G-CSF comprises G-CSF, either of natural or recombinant origin, and also modified forms thereof, e.g., fusions or conjugates, as long as the modified version can still maintain the basic biological activity of G-CSF, in particular the stimulation of the production of neutrophils.
  • modified forms of G-CSF have therapeutically advantageous features.
  • a well-known modification of G-CSF is the coupling to water-soluble polymers, e.g., polyethylene glycols or polypropylene glycols.
  • Modified G-CSFs and their preparation are described, e.g., in EP 401 384, EP 335 423 and EP 473 268.
  • Modified G-CSF also comprises, e.g., G-CSF which shows a different glycosylation pattern as known for naturally occurring or recombinant G- CSF in the form of at least one additional polycarbohydrate chain as described, e.g., in EP 370 205.
  • Fusion proteins of G-CSF are for example fusions to albumin, such as albugranin and balugrastim.
  • the term includes filgrastim, lenograstim, pegfilgrastim and lipegfilgrastim.
  • G-CSF is a modified G-CSF form, such as a G-CSF fusion protein, pegylated G- CSF or G-CSF with a modified glycosylation pattern or combinations thereof. More preferably, the G-CSF is a pegylated G-CSF. In some embodiments the G-CSG is selected from the group consisting of filgrastim, pegfilgrastim, lenograstim and lipegfilgrastim. More preferably, the G-CSF is pegfilgrastim.
  • Human G-CSF is a 174 amino acid (aa) protein.
  • the protein sequence of the human G-CSF is depicted in SEQ ID NO: 1.
  • the term G-CSF therefore includes peptides comprising the sequence of SEQ ID NO: 1 or a sequence which is at least 90 %, or at least 95 %, or at least 97 % identical to said sequence, as long as the peptides show the basic biological activity of G-CSF, in particular the ability to increase the number of neutrophils in the blood.
  • a sequence which is at least 90 % identical to said sequence comprises amino acid deletions, amino acid substitutions or amino acid replacements. In particular, the addition or deletions of glycosylation sites is considered.
  • Pegfilgrastim is a pegylated human granulocyte-colony stimulating factor (G-CSF) with a single 20 kDa polyethylene glycol (PEG) that acts in the same manner as the endogenous G- CSF protein to stimulate the production of neutrophil precursors and the differentiation and release of mature neutrophils.
  • G-CSF human granulocyte-colony stimulating factor
  • PEG polyethylene glycol
  • Pegfilgrastim is a sustained duration form of filgrastim, due to decreased renal clearance. Pegfilgrastim and filgrastim have been shown to have identical modes of actions, causing a marked increase in peripheral blood neutrophil counts within 24 hours, with minor increases in monocytes and/or lymphocytes.
  • B 12019 is a long-acting, pegylated form of recombinant human granulocyte-colony stimulating factor (r-metHuG-CSF, filgrastim) for the prevention of chemotherapy-induced neutropenia.
  • r-metHuG-CSF granulocyte-colony stimulating factor
  • the G-CSF containing composition may comprise besides G-CSF other compounds, for example excipients, diluents, stabilizers (such as proteins, for example human serum albumin), anti-adsorption agents, preservatives, solubilizers and/or emulsifiers as described, e.g., in DE 37 23 781.
  • the G-CSF containing composition may or may be in the form of a stabilized hydrophobic formulation as described e.g. in EP 373 679 or in the form of a sustained release particulate preparation as described, e.g., in EP 263 490 or for pegylated G- CSF as described, e.g., in EP 473 268.
  • a decrease of the blood glucose level after administration of the G-CSF containing composition indicates that the G-CSF containing composition is efficacious.
  • the G-CSF containing composition will show a treatment effect, e.g. lead to the amelioration of the symptoms of fibrile neutropenia and/or the increase of neutrophils in the subject, e.g. patient to which G-CSF was administered.
  • the terms "efficacy” or “efficacious” as used herein mean that the G-CSF containing composition shows a treatment effect, e.g.
  • the subject to which the G-CSF containing composition is administered may be a healthy person or a patient. For example, new G-CSF compositions or new G-CSF variants may be tested in healthy persons.
  • the therapy with G-CSF composition may be maintained or adapted, i.e. by increasing or decreasing the administered amount, by switching the G-CSF composition or by quitting the treatment with the G-CSF composition.
  • the subject may be a patient suffering from neutropenia.
  • the subject may be a patient that is suffering from fibrile neutropenia. Usually the neutropenia is caused by cytotoxic chemotherapy which the subject receives.
  • the measurement of the blood glucose level after the administration of the G-CSF containing composition may be carried out in a time interval in which the glucose concentration is expected to be lowered. Therefore, the sample collection after the administration of the G- CSF containing composition may be at least 12 hours, at least 24 hours, at least 36 hours, at least 48 hours after the administration.
  • the blood glucose measurement may occur for 12 hours to 144 hours after the administration of the G-CSF containing composition, or 24 hours to 120 hours after the administration.
  • the measurement of the blood glucose level after the administration of the G-CSF containing composition is carried out 36 h to 72 h after the administration of the G-CSF containing composition, even more preferably about 48 hours after the administration of the G-CSF containing composition.
  • the term "measurement of the blood glucose level” includes also the measurement at several time points. More specifically, this includes the measurement of the blood glucose level at several time points before the administration and/or at several time points after the administration of the G-CSF containing composition.
  • the measurement of the blood glucose level may be at at least one time point before the administration of the G-CSF containing composition and at least one time point after the administration. That means that the blood glucose level may be measured in at least one sample obtained before the administration of the G-CSF containing composition and in at least one sample obtained after the administration of the G-CSF containing composition.
  • when G-CSF is administered over a longer time course it may be useful to monitor the efficacy over time in order to assess whether the G-CSF containing composition still shows its treatment effect. Thereby, the values of the different time points may be
  • blood glucose values of several time points may be averaged.
  • G-CSF containing composition may be averaged. Accordingly, the blood glucose values of several samples obtained after administration of the G-CSF containing composition may be averaged.
  • At least one sample thus refers to at least 2, at least 3, at least 4, at least 5 or more samples.
  • the reference sample i.e. the at least one sample obtained before the administration of the G-CSF containing solution
  • the reference sample is obtained from the same subject as the at least one sample obtained after the administration of the G-CSF containing solution.
  • a decrease of the blood glucose level below a predetermined threshold after the administration of the G-CSF containing composition level indicates that the G-CSF containing composition is efficacious.
  • the blood glucose level of less than 4.5 mmol/1, preferably less than 4.25 mmol/1, more preferably less than 4.0 mmol/1 under fasting conditions may indicate that the G-CSF containing composition is efficacious.
  • a decrease of the blood glucose level by a predetermined value or predetermined percentage after the administration of the G-CSF containing composition indicates that the G-CSF containing composition is efficacious. That means that a decrease of the blood glucose level of the at least one sample obtained from the subject after the administration of G-CSF in comparison to the blood glucose level of the at least reference sample of the subject (e.g. a sample obtained from the subject before the administration of the G-CSF containing composition) indicates that the G-CSF containing composition is efficacious.
  • a blood glucose level decrease by at least by 0.4 mmol/1, preferably by at least 0.5 mmol/1, at least 0.6 mmol/1, at least 0.7 mmol/1 more preferably by at least 0.8 mmol/1, at least 0.9 mmol/1 even more preferably by at least 1 mmol/1 may indicate that the G-CSF containing composition is efficacious.
  • a blood glucose level decrease by at least 0.4 mmol/1, preferably by at least 0.5 mmol/1, more preferably by at least 0.8 mmol/1, even more preferably by at least 1 mmol/1 when the glucose level is measured 24 h to 72 h after administration of the G-CSF containing composition may indicate that the G-CSF containing composition is efficacious.
  • the blood glucose level decrease by at least 5 %, preferably by at least 10 %, more preferably by at least 15 %, even more preferably by at least 20 % may indicate that the G-CSF containing composition is efficacious.
  • administration of the G-CSF containing composition may indicate that the G-CSF containing composition is efficacious.
  • the blood glucose level may be measured under fasting or non-fasting conditions.
  • the blood glucose level before and after administration is typically measured under the same conditions, i.e. fasting or non-fasting conditions. That means that if the blood glucose level before the administration is measured under fasting conditions, then the blood glucose level after the administration is also measured under fasting conditions. Correspondingly, if the blood glucose level before the administration is measured under non- fasting conditions, then the blood glucose level after the administration is measured under non- fasting conditions. If possible, the blood glucose level is measured under fasting conditions. Fasting conditions mean that for at least 6 hours, preferably at least 8 hours, more preferably at least 10 hours no food uptake has occurred. If the blood glucose level is measured at several time points under non- fasting conditions, it is advantageous that the food up-take before the different measurements, e.g. 12 hours, 9 hours, 6 hours or 3 hours before the measurement of the blood glucose level is similar, e.g. similar amount of calories in a similar food composition is digested.
  • the blood glucose level may be for example measured by blood glucose meters, blood glucose assay kits (e.g. provided by Abeam, UK) or assay platforms applying the respective tests (such as GLUC 3 Glucose HK test for the cobas® platform by Roche) that are available on the market.
  • blood glucose assay kits e.g. provided by Abeam, UK
  • assay platforms applying the respective tests such as GLUC 3 Glucose HK test for the cobas® platform by Roche
  • the invention also refers to a method for determining the efficacy of a granulocyte-colony stimulating factor (G-CSF) containing composition, comprising the steps measurement of the blood glucose level of a sample obtained from a subject to which a G-CSF containing composition was administered and determining the efficacy of the G-CSF containing composition based on the blood glucose level.
  • G-CSF granulocyte-colony stimulating factor
  • the method comprises the steps measurement of the blood glucose level of a blood sample that was obtained from a subject before the administration of the G-CSF containing composition, measurement of the blood glucose level of a blood sample that was obtained from said subject after the administration of the G-CSF containing composition and determining the efficacy of the G-CSF containing composition based on the blood glucose level.
  • kits for the measurement of the efficacy of a G-CSF containing composition may comprise compounds suitable for the determination of the blood glucose level in a subject.
  • Study design Randomised, double-blind, two-stage, two-way crossover, with sequential subcutaneous (s.c.) administration of single doses of 6 mg B12019 and 6 mg Neulasta® (or vice versa). Subjects were allocated at random to sequentially receive B12019 and Neulasta® or vice versa. The washout phase between the treatments (dosing for period 1 and dosing for period 2) was 6 weeks, corresponding to approximately 15 half- life times of the compound.
  • the study methodology was based on a two-stage design planning for a sample size re-calculation after completion of stage 1 and potential sample size adjustment for stage 2. According to the predefined decision rules, no stage 2 was performed.
  • Blood samples for analytical assay were collected during the stationary phase at Day 1 : pre- dose, 4h, 8h, 12h, 16h; Day 2: 24h, 36h; Day 3: 48h, 60h; Day 4: 72h, 84h; Day 5: 96h after administration in each period (12 samples), during the ambulatory visits on Days 6, 7, 8, 10, 12, 15, 18, 22, 29 and on Day 43 in each period (10 samples).
  • Serum samples were analyzed for pegfilgrastim concentration using a validated ELISA assay.
  • Blood samples to determine the absolute neutrophil counts were collected during the in-patient phase at Day 1 : pre-dose, 12h, Day 2: 24h, 36h; Day 3: 48h, 60h; Day 4: 72h, 84h; Day 5: 96h after administration in each period (9 samples), during the ambulatory visits on Days 6, 7, 8, 10, 12, 15, 18, 22, 29 and on Day 43 in each period (10 samples).
  • the blood glucose level was determined in blood samples collected at study days -1, 3, 8, 15, 22 and 29 and 43 per period under fasting conditions.
  • the blood glucose level was determined by a hexokinase assay using the cobas® platform by Roche GLUC 3 Glucose HK).
  • hexokinase catalyzes the phosphorylation of glucose by TAP forming G-6-P and ADP; a second enzyme catalyzes the oxidation of G-6-P by NAD+ to form NADH; The absorbance is measured at 340 nm.
  • Eligibility subject were mild or non- smoking subjects, between 18 and 55 years of age inclusive, with a body mass index (BMI) between 20.0 and 30.0 kg/m 2 inclusive and a weight between 60 and 100 kg inclusive.
  • BMI body mass index
  • the maximum individual decrease was -3.28 mmol/L observed in Subject 105 in Period 1 after Neulasta® (from 5.86 mmol/L pre-dose to 2.58 mmol/L at 48 hours after dosing; glucose returned to 5.07 on Day 8).
  • hypoglycaemia No symptomatic hypoglycaemia occurred.
  • Hypoglycaemia was reported as AE for 37 subjects (21.6%) after Neulasta® and for 33 subjects (19.3%) after B12019.
  • the intensity was mainly assessed as moderate (35 subjects [20.5%>] after Neulasta® and 29 subjects [17.0%] after B 12019) per the defined threshold).
  • Hypoglycaemia of severe intensity was not observed. None of these hypoglycaemia cases were associated with clinical signs or symptoms or required intervention.

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Abstract

La présente invention concerne un procédé de détermination de l'efficacité d'une composition contenant le facteur de stimulation des colonies de granulocytes (G-CSF) comprenant les étapes d'administration de la composition contenant le G-CSF à un sujet, de mesure du taux de glycémie dudit sujet et de détermination de l'efficacité de la composition contenant leG-CSF sur la base du taux de glycémie.
PCT/EP2018/051965 2017-01-27 2018-01-26 Procede de determination de l'efficacite d'une composition comprenant le g-csf WO2018138267A1 (fr)

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EP0373679A2 (fr) 1988-12-16 1990-06-20 Amgen Inc. Formulations stabilisées à base de protéines hydrophobes
EP0401384A1 (fr) 1988-12-22 1990-12-12 Kirin-Amgen, Inc. Facteur de stimulation de colonies de granulocytes modifies chimiquement
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WO2002020767A2 (fr) * 2000-09-08 2002-03-14 Massachusetts Institute Of Technology Composition d'analogue du g-csf et procede associe
US20130164252A1 (en) * 2011-12-23 2013-06-27 Saref Technologies, Inc. Method for Hair Growth using Granulocyte-Colony Stimulating Factor
US20130251669A1 (en) * 2010-10-19 2013-09-26 Advanced Neuroregenerative Therapies, Llc Treatment of diabetes using g-csf and hyperbaric oxygen
US20150118185A1 (en) * 2008-03-19 2015-04-30 The Board Of Regents Of The University Of Oklahoma Heparosan-Polypeptide and Heparosan-Polynucleotide Drug Conjugates and Methods of Making and Using Same

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US4179337A (en) 1973-07-20 1979-12-18 Davis Frank F Non-immunogenic polypeptides
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